This program project renewal application is an integrated multidisciplinary program including four closely related projects examining the roles of stress, lifestyle behaviors and genetic predisposition in the development of preclinical measures of essential hypertension. New to the renewal application will be the incorporation of adiposity as a mediating factor into our gene/environment interaction model. Four vasoactive pathways will be examined which may link impaired sodium regulation during stress and exaggerated cardiovascular reactivity to stress to the development of preclinical measures of hypertension. These pathways are the sympathetic nervous system, the renin-angiotensin-aldosterone system, the endothelial system, and the hypothalamic-pituitary-adrenal axis. Specifically, Projects 1 and 4 will focus on the role of the renin-angiotensin-aldosterone system in human and animal models of stress-induced salt sensitive hypertension. Projects 2 (human) and 3 (animal) will continue in the evaluation of blood pressure hyper-reactivity. Project 2 will continue to evaluate this model in a cohort of subjects with a family history of hypertension that will have been continuously evaluated for 22 years. Also, new to this application will be evaluation of the hypothalamic-pituitary-adrenal axis. Project 3 will use air jet stress in Dahl salt-sensitive rats to examine acute changes in endothelin and oxidative stress. All four projects will examine a potential mediating role of increased adiposity. In addition, each of these four projects will be supported by an Administrative (Core A), Bioassay (Core B), Biomedical (Core C), and Data Management and Statistics (Core D) cores. Relevance to public health: High blood pressure, or hypertension, remains a significant health problem in industrialized nations. The results of this study will help further define the interactive effects of genetic predisposition and environmental stress in the development of hypertension, particularly in overweight individuals. The pharmacologic and pharmacogenetic interventions will provide evidence for effective management of stress-related hypertension.